Cyclic peptide antibiotics

Abstract

Provided herein are antibacterial compound peptides active against Gram-negative bacteria. In various embodiments, the compounds act by inhibition of BAM A membrane protein. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

We claim: 
     
         1 . A compound of formula I 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1-6  alkyl, hydroxyl-C 1-6 alkyl or benzyl optionally substituted with halogen or hydroxy; 
 R 1a  is hydrogen; 
 R 2  is hydrogen, C 1-6  alkyl or optionally substituted (imidazol-4-yl)methyl; 
 R 3  is bicyclic aryl, bicyclic heteroaryl, C 1-6 alkyl, or hydroxyl-C 1-6 alkyl wherein the bicyclic aryl and bicyclic heteroaryl is optionally substituted once or twice with C 1-6 alkyl, hydroxyl or halo; 
 R 3a  is hydrogen or C 1-6 alkyl; 
 R 4  is C 1-6 alkyl or optionally substituted (imidazol-4-yl)methyl; 
 R 5  is hydrogen; C 1-6 alkyl, hydroxyl-C 1-6 alkyl, optionally substituted (imidazol-4-yl)methyl or optionally substituted guanidino-C 2-4 alkyl; 
 R 6  is hydroxyl-C 1-6 alkyl or amino-C 1-6 alkyl; 
 R 7  is C 1-6 alkyl, hydroxyl-C 1-6 alkyl or optionally substituted guanidino-C 2-4 alkyl 
 R 8  is optionally substituted benzyl; 
 R 8a  is hydrogen or C 1-6 alkyl; 
 R 9  is optionally substituted benzyl or optionally substituted 1H-imidazol-5-ylmethyl; 
 R 10  is C 1-6 alkyl, amino-C 1-6 alkyl, optionally substituted 1H-imidazol-5-ylmethyl, optionally substituted guanidino-C 2-4 alkyl or optionally substituted C 1-2 alkyl-carboxamide; 
 R 11  is optionally substituted benzyl or optionally substituted (imidazol-4-yl)methyl; 
 R 12  is N-(3-amino-3-oxo-propyl)carboxamide or N-(2-amino-2-oxo-ethyl)carboxamide both optionally substituted; 
 R b , R c , R d , R e , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i , R 15j , R 15k , R 16a , R 16b , R 16c  and R 16d  are each independently hydrogen, or C 1-6 alkyl; 
 R 15e  is hydrogen, C 1-6 alkyl, amino-C 1-6 alkyl, or optionally substituted C 1-2 alkyl-carboxamide; 
 R a  is hydrogen, C 1-6 alkyl, hydroxyl or halo; 
 n and p are independently from 0 to 2; 
 q is 0 or 1; and, 
 r is 1 or 2. 
 
       
     
     
         2 . The compound of  claim 1  wherein R 12  is N-(2-amino-2-oxo-ethyl)carboxamide, R 4  and R 9  are 1H-imidazol-5-ylmethyl and R 2  is C 1-6  alkyl. 
     
     
         3 . The compound of either of  claim 1 or 2  wherein:
 R 1  is C 1-6 alkyl, hydroxyl-C 1-6 alkyl or optionally substituted benzyl; 
 R 3  is 1-naphthylmethyl, 2-naphthylmethyl, (4-phenylphenyl)methyl or optionally substituted 1H-indolyl-3-methyl; 
 R 5  is hydrogen, or 3-guanidopropyl; 
 R 6  is hydroxyl-C 1-6 alkyl or 4-aminobutyl; 
 R 7  is 3-guanidopropyl; 
 R 10  is 3-guanidino-propyl, methyl, ethyl, aminomethyl, aminoethyl, 4-aminobutyl, 3-methylimidazol-4-yl)methyl or 3-amino-3-oxo-propyl; 
 R 11  is 1H-imidazol-5-ylmethyl or 3-methylimidazol-4-yl)methyl; 
 R b , R c , R e , R 1a , R 3a , R 8a , R 15b , R 15c , R 15d , R 15f , R 15g , R 15i , R 15k , R 16a , R 16b , R 16c  and R 16d  are hydrogen; 
 R 15a , R 15e , R 15h  and R 15j  are independently hydrogen or methyl; 
 R b  and R f  are independently hydrogen or methyl; 
 R 15h  is methyl; 
 or, a stereoisomer or a pharmaceutically acceptable salt thereof. 
 
     
     
         4 . The compound of any of  claims 1 to 3  wherein:
 R 1  is benzyl optionally substituted halogen or hydroxy; 
 R 2  is hydrogen, ethyl, isopropyl or (1S)-1-methylpropyl; 
 R 3  is 1-naphthylmethyl or 1H-indole-3-methyl; 
 R 4  is 1H-imidazol-5-ylmethyl; 
 R 5  is hydrogen; 
 R 6  is hydroxymethyl or (1R)-1-hydroxyethyl; 
 R 7  is 3-guanidinopropyl; 
 R 8  is benzyl or 4-hydroxybenzyl; 
 R 9  is 1H-imidazol-5-ylmethyl; 
 R 10  is 3-guanidopropyl, methyl or ethyl; 
 R 11  is 1H-imidazol-5-ylmethyl, 3-methylimidazol-4-yl)methyl; 
 R 12  is —C(═O)NHCH 2 C(═O)NH 2 ; 
 or, a stereoisomer or a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . The compound of any of  claims 1 to 4  wherein:
 R 1  is benzyl; 
 R 2  is ethyl or isopropyl; 
 R 3  is 1-naphthylmethyl; 
 R 4  is 1H-imidazol-5-ylmethyl; 
 R 5  is hydrogen; 
 R 6  is hydroxylmethyl; 
 R 7  is 3-guanidopropyl; 
 R 5  is 4-hydroxylbenzyl or 4-chlorobenzyl; 
 R 9  is 1-methyl-1H-imidazole-5-methylene; 
 R 10  is 3-guanidopropyl; 
 R 11  is (3-methylimidazol-4-yl)methyl; 
 R 12  is N-(2-amino-2-oxo-ethyl)carboxamide; 
 R b  and R f  are independently in each occurrence hydrogen or methyl; and, 
 
       or a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of any one of  claims 1 to 5  wherein the compound is of formula Ia; 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound according to any one of  claims 1 to 6  wherein said compound is selected from TABLE 1. 
     
     
         8 . A compound of Formula (II) 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is optionally substituted benzyl; 
 R 1a  is hydrogen or C 1-6 alkyl; 
 R 2  is hydrogen or optionally substituted (imidazol-4-yl)methyl; 
 R 3  is C 1-6 alkyl or hydroxyl-C 1-6 alkyl; 
 R 3a  is hydrogen or C 1-6 alkyl; 
 R 4  is C 1-6 alkyl or optionally substituted (imidazol-4-yl)methyl; 
 R 5  is optionally substituted guanidino-C 2-4 alkyl or optionally substituted (imidazol-4-yl)methyl; 
 R 6  is amino-C 1-6 alkyl or optionally substituted guanidino-C 2-4 alkyl; 
 R 7  is hydroxyl-C 1-6 alkyl or optionally substituted guanidino-C 2-4 alkyl; 
 R 8  is methyl or 3-propylguanidine; 
 R 8a  is hydrogen or methyl; 
 R 9  is optionally substituted benzyl; 
 R 10  is amino-C 1-6 alkyl, optionally substituted (imidazol-4-yl)methyl or optionally substituted guanidino-C 2-4 alkyl; 
 R 11  is optionally substituted benzyl; 
 R 12  is indolyl-3-methyl or optionally substituted benzyl; 
 R 13  is optionally substituted benzyl; 
 R 14  is N-(3-amino-3-oxo-propyl)carboxamide or N-(2-amino-2-oxo-ethyl)carboxamide both optionally substituted; 
 R b , R c , R d , R e , R f , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i , R 15j , R 15k , R 15l , R 15m , R 15n , R 16a , R 16b , R 16c  and R 16d  are in each occurrence independently hydrogen or C 1-6 alkyl; 
 R a  is hydrogen, C 1-6 alkyl, hydroxyl or halo; 
 n and p are each independently 0 to 2; and 
 q is 0 or 1. 
 
       
     
     
         9 . The compound of  claim 8 , wherein:
 R 1  is optionally substituted benzyl;   R 1a  is hydrogen or C 1-6 alkyl;   R 2  is (3-methylimidazol-4-yl)methyl;   R 3  is C 1-6 alkyl or hydroxyl-C 1-6 alkyl;   R 3a  is hydrogen or C 1-6 alkyl;   R 4  is C 1-6 alkyl;   R 5  is 3-guanidino-propyl;   R 6  is 3-guanidino-propyl or amino-C 1-6 alkyl;   R 7  is 3-guanidino-propyl or hydroxyl-C 1-6 alkyl;   R 8  is optionally substituted benzyl;   R 8a  is methyl;   R 9  is optionally substituted benzyl;   R 10  is optionally substituted guanidino-C 2-4 alkyl, (3-methylimidazol-4-yl)methyl or amino-C 1-6 alkyl;   R 11  is 4-hydroxybenzyl or 4-chlorobenzyl;   R 12  is 1H-indole-3-methyl or 4-chlorobenzyl;   R 13  is optionally substituted benzyl;   R 14  is —C(═O)NHCH 2 C(═O)NH 2 ;   R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i , R 15j , R 15k , R 15l , R 15m , R 15n , R 16a , R 16b , R 16c  and R 16d  are hydrogen;   
       or, a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of either  claims 8 or 9 , wherein:
 R 1  is benzyl;   R 1a  is hydrogen;   R 2  is (3-methylimidazol-4-yl)methyl;   R 3  is methyl or (1R)-1-hydroxyethyl;   R 3a  is hydrogen or methyl;   R 4  is (1S)-1-methylpropyl;   R 5  is 3-guanidopropyl;   R 6  is 4-amino-butyl;   R 7  is 3-guanidopropyl or -(1R)-1-hydroxyethyl;   R 8  and R 8a  are methyl;   R 9  is benzyl;   R 10  is guanidino-propyl, (3-methylimidazol-4-yl)methyl or amino-C 1-6 alkyl;   R 11  is 4-hydroxybenzyl;   R 12  is 1H-indole-3-methyl;   R 13  is 4-hydroxybenzyl;   R 14  is —C(═O)NHCH 2 C(═O)NH 2 ;   R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i , R 15j , R 15k , R 15l , R 15m , R 15n , R 16a , R 16b , R 16c  and R 16d  are hydrogen;   
       or, a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of any of  claims 8 to 10 , wherein:
 R 1  is benzyl;   R 1a  is hydrogen;   R 2  is (3-methylimidazol-4-yl)methyl;   R 3  is methyl or (1R)-1-hydroxyethyl;   R 4  is (1S)-1-methylpropyl;   R 5  is 3-guanidino-propyl;   R 6  is 4-aminobutyl;   R 7  is rac-(1R)-1-hydroxyethyl;   R 8  and R 8a  are methyl;   R 9  is benzyl;   R 10  is 3-guanidinopropyl, (3-methylimidazol-4-yl)methyl, aminomethyl, 2-amino-ethyl, 3-aminopropyl or 4 aminobutyl;   R 11  is 4-hydroxybenzyl;   R 12  is 1H-indole-3-methyl;   R 13  is 4-hydroxybenzyl;   R 14  is —C(═O)NHCH 2 C(═O)NH.   
     
     
         12 . The compound of any of  claims 8 to 11 , wherein:
 R 1  is benzyl;   R 1a  is hydrogen;   R 2  is (3-methylimidazol-4-yl)methyl;   R 3  is methyl or (1R)-1-hydroxyethyl;   R 4  is (1S)-1-methylpropyl;   R 5  is 3-guanidino-propyl;   R 6  is 4-aminobutyl;   R 7  is rac-(1R)-1-hydroxyethy;   R 8  and R 8a  are methyl;   R 9  is benzyl;   R 10  is 3-guanidinopropyl:   R 11  is 4-hydroxybenzyl;   R 12  is 1H-indole-3-methyl;   R 13  is 4-hydroxybenzyl;   R 14  is —C(═O)NHCH 2 C(═O)NH;   or, a stereoisomer or a pharmaceutically acceptable salt thereof.   
     
     
         13 . The compound of any of  claims 8 to 11 , wherein:
 R 1  is benzyl;   R 1a  is hydrogen;   R 2  is (3-methylimidazol-4-yl)methyl;   R 3  is methyl or (1R)-1-hydroxyethyl;   R 4  is (1S)-1-methylpropyl;   R 5  is 3-guanidino-propyl;   R 6  is 4-aminobutyl;   R 7  is rac-(1R)-1-hydroxyethy;   R 5  and R 8a  are methyl;   R 9  is benzyl;   R 10  is (3-methylimidazol-4-yl)methyl;   R 11  is 4-hydroxybenzyl;   R 12  is 1H-indole-3-methyl;   R 13  is 4-hydroxybenzyl;   R 14  is —C(═O)NHCH 2 C(═O)NH;   or, a stereoisomer or a pharmaceutically acceptable salt thereof.   
     
     
         14 . The compound of any of  claims 8 to 11 , wherein:
 R 1  is benzyl;   R 1a  is hydrogen;   R 2  is (3-methylimidazol-4-yl)methyl;   R 3  is methyl or (1R)-1-hydroxyethyl;   R 4  is (1S)-1-methylpropyl;   R 5  is 3-guanidino-propyl;   R 6  is 4-aminobutyl;   R 7  is rac-(1R)-1-hydroxyethy;   R 8  and R 8a  are methyl;   R 9  is benzyl;   R 10  is 3-aminopropyl or 4 aminobutyl;   R 11  is 4-hydroxybenzyl;   R 12  is 1H-indole-3-methyl;   R 13  is 4-hydroxybenzyl;   R 14  is —C(═O)NHCH 2 C(═O)NH;   
       or, a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of any of  claims 8 to 14  wherein the compound is of formula IIa 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound according to any one of  claims 7 to 15  wherein said compound is selected from TABLE 2. 
     
     
         17 . A pharmaceutical composition comprising the compound of any one of  claims 1 to 16 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. 
     
     
         18 . Use of a compound of any one of  claims 1 to 16 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for preparation of a medicament for the treatment of a bacterial infection in a patient. 
     
     
         19 . A method of treatment of a bacterial infection in a mammal, comprising administering to the mammal an effective amount of a compound of any one of  claims 1 to 16 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the mammal at a frequency and for a duration sufficient to provide a beneficial effect to the mammal. 
     
     
         20 . A method of treatment of a gram negative mediated infection in a mammal, comprising administering to the mammal an effective amount of a compound of any one of  claims 1 to 16 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the mammal at a frequency and for a duration sufficient to provide a beneficial effect to the mammal. 
     
     
         21 . The method of  claim 19 or 20 , wherein the bacterial infection is an infection involving  E. coli.    
     
     
         22 . The method of any one of  claims 19 to 21  further comprising administering a second therapeutic agent. 
     
     
         23 . The method of  claim 22 , wherein the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, β-lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid.